The significant mortality of pathogenic avian influenza strains appears to be due to their propensity to induce severe cytokine-mediated immune pathology. Even in seasonal influenza, cytokine production correlates with severity of symptoms. For this reason, therapies that reduce immune pathology would be expected to significantly reduce the morbidity and mortality associated with human avian influenza infection. At a minimum, such strategies may keep patients alive until viral infection can be controlled by other means. The immune pathology that occurs during influenza infection is due, in large part, to the accumulation of specific inflammatory cell populations in the lung. This accumulation is driven by a small number of inflammatory chemokines, molecules that attract specific cell types to areas of inflammation. In preliminary studies, we have found that mice lacking a specific chemokine receptor display markedly reduced morbidity and mortality during influenza infection and define the mechanism by which this occurs. These findings strongly suggest that the mortality of avian influenza infection could be substantially lessened using a specific chemokine receptor antagonist. Importantly, a pharmacologic antagonist for the chemokine receptor we have identified has already been developed and proven to be safe and effective in early clinical trials for other indications. This raises the possibility that a drug already exists that would reduce the morbidity and mortality of avian influenza infection in humans. In a series of animal studies, we will examine the ability of the chemokine receptor antagonist to recapitulate the beneficial effects seen in receptor-deficient mice. We will determine if the antagonists is efficacious when administered after infection is established, the time window in which the antagonist is beneficial, and if the antagonist ameliorates the pathologies associated with human avian influenza infection. In additional studies, we will examine the potential deleterious effects of the antagonist on immune responses and the control of virus replication, and test the antagonist during infection with a true avian influenza strain. These studies will provide a basis for determining if trials of chemokine receptor antagonists should be considered in humans. [unreadable] [unreadable] [unreadable] [unreadable]